This proposal is concerned with chemical synthesis of novel nucleoside analogs as potential antimetabolites acting as cancer inhibitors, and for their biological evaluation. Following leads of compounds already prepared in our laboratory that show activity in the L-1210 leukemia and other screens, it is proposed to design and synthesize analogs structurally related to known antimetabolities such as sugar derivatives of 6-mercaptopurine, 5-fluorouracil, and 5-azacytosine, and the nucleosides arabinofuranosylcytosine, arabinofuranosyladenine, puromycin, toyocamycin, and formycin. The analogs will emphasize stereochemical and substitutional variants in the sugar portion, with particular stress on systems having an acyclic sugar chain potentially isosteric with the beta-D-pentofuranosyl groups. The products will be evaluated for cytotoxicity, for in vivo antitumor activity, for cell penetration, and for antiviral activity, and their behavior with catabolic and anabolic enzymes will be studied. The biological results will be used to guide the synthetic approaches to new agents. Selected agents of high promise will be examined in detail to assess their mode of action, by use of isotopically labeled analogs and other techniques.